Safinamide | Monoamine Oxidase B Inhibitors | Treatment for Parkinson’s Disease

Safinamide [(S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide] is an oral α-aminoamide derivative developed for the treatment of Parkinson’s disease (PD). It is a potent, highly selective and reversible inhibitor of monoamine oxidase B (MAO-B) and reduces dopamine reuptake {dopaminergic properties}. It also blocks voltage dependent sodium channels by preferentially interacting with the inactivated channel, modulates N-type calcium channels and reduces glutamate release {non-dopaminergic properties}. Thus, this unique combination of two modes of actions offers the potential of a symptomatic relief of motor features in PD patients in one drug [1-3].

The activity of drug has been credited to presence of both dopaminergic properties and non-dopaminergic properties, though the exact use of this activity-combination is still unknown. Still, Safinamide is considered as a potent addition to the arsenal answering the unmet needs for treating PD, and related conditions.

Safinamide: 2D and 3D Structutre

Safinamide is a small, water-soluble molecule, which is chemically and metabolically stable. It combines low CNS toxicity, excellent bioavailability, linear kinetics and a long half-life. Its favorable pharmacokinetics and pharmacodynamics makes it possible for a once-daily oral dosing.

In February 2015, Safinamide was approved in the EU for the treatment of mid- to late-stage fluctuating PD, as an add-on to Levodopa (L-dopa), alone or in combination with other PD medications. The approval is applicable to the EU member states, as well as Iceland, Lichtenstein and Norway; regulatory submissions have also been filed in the USA and Switzerland for its use in this indication.

Parkinson’s disease (PD) and Treatments:

After Alzheimer’s disease (AD), Parkinson’s disease (PD) is one of the most common neurodegenerative disease faced by the elderly. PD is characterized by the classically defined motor symptoms of tremor, bradykinesia, rigidity and postural instability. Various non-motor symptoms (NMS) that may proceed (e.g., constipation, hyposmia, rapid eye movement sleep behavioral disorder) or accompany (cognitive, sweating, sleep disturbances) motor symptoms or may occur at later stages of the disease (autonomic disturbances). Though PD itself is not life threatening but NMS can cause fatal injuries [2].

The exact pathophysiology of PD is unclear, but it is well known that in PD, the neurodegeneration is widespread. The degeneration of substantia nigra dopaminergic (DA) neurons causes motor symptoms, while NMS results from loss of cells with various neurotransmitters. Moreover, there is accumulation of an insoluble protein α-synuclein in the area involved; forming Lewy bodies which may lead to cell damage. The damage seems to be enhanced by other mechanisms such as proteosomal and lysosomal system dysfunction, reduced mitochondrial activity, inflammation, glutamate excitotoxicity and oxidative stress.

In simple word: In patients with Parkinson’s disease, certain cells in the brain that produce dopamine die, and as dopamine is involved in controlling movement, the patient's movement worsens over time. The treatment of the disease is mainly symptomatic.

As the motor symptoms and many NMS result from the loss of dopaminergic neurons, dopamine replacement forms the cornerstone of therapy.

Dopamine is a monoamine neurotransmitter and human body synthesize it via the food we intake. Tyrosine which is available in our diet is converted to Levodopa which is decarboxylated to dopamine in the neurons. Once the dopamine is released into the synaptic cleft, it is metabolized by monoamine-oxidase B (MAO-B) enzyme and in the postsynaptic neurons by catechol-O-methyl transferase (COMT). Thus, dopaminergic replacement drugs include Levodopa (most commonly used drug to treat PD), dopamine agonists (DAs, such as Bromocriptine, Lisuride, Pramipexole, Ropinirole, etc) and drugs preventing dopamine metabolism – peripheral COMT inhibitors (COMTIs, such as Tolcapone and Entacapone) and MAO-B inhibitors (MAO-BIs, such as Selegiline, Rasagiline, and now Safinamide).

Levodopa and DA therapy though very effective are marred with serious adverse events including increased dyskinesias, gastrointestinal and sleep/fatigue-related adverse events. Compared with Levodopa and DA therapy, MAO-BIs have weaker symptomatic benefit but lesser side effects. This makes them perfect candidate for monotherapy in early stages and as adjunctive to Levodopa in later stages of the disease [4].

Mechanism of Action in Safinamide:

Safinamide is a selective and reversible inhibitor of monoamine oxidase-B (MAO-B) and blocks dopamine reuptake. Monoamino oxidases (MAOs) are flavin adenine dinucleotide (FAD) containing enzymes localized in the outer mitochondrial membrane. MAOs are involved in the oxidative deamination of important endogenous amines, including monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA), as well as exogenous amines, comprising the hypertensive dietary amine tyramine [3,4].

Two different isoenzymatic forms have been identified, namely, MAO-A and MAOB, which differ in their amino acid sequences, three-dimensional structures and substrate specificity and sensitivity to inhibitors. MAO-A preferentially deaminates noradrenaline and serotonin while MAO-B shows affinity for benzylamine and phenylethylamine. Monoamines, for example, dopamine, are substrates of both isoforms.

Reversible inhibitors of MAO-A are an effective treatment approach for depression. Selective inhibitors of MAO-B are used for the treatment of PD patients, since they prolong dopamine activity in the synaptic cleft of dopaminergic neurons. They are used in addition to Levodopa either alone or in combination with other medicines for Parkinson’s, in patients with mid- to late-stage Parkinson’s disease who are having ‘motor fluctuations’. These fluctuations occur when the effect of Levodopa wears off and the patient suddenly switches from being ‘on’ and able to move about to being ‘off’ and having difficulty moving about [5].

Other Activities:

Antiglutamate effect: Safinamide blocks voltage-dependent fast sodium channels. It has a prefential interaction with the inactivated sodium channel and prevents its recovery to the active state. Safinamide also modulates N-type calcium channels. Both mechanisms have been considered to reduce glutamate release and NMDA receptor stimulation. The inhibition of glutamate can reduce dyskinesias similar to drug amantadine and protect against excitotoxicity.

Neuroprotective effects: As common with all other MAO-BIs, Safinamide has shown neuroprotective effects in animal and tissue culture models.

Dose-related improvement in motor symptoms on using Safinamide have been postulated to its combined ability for inhibition of glutamate release, increased dopamine release and inhibition of reuptake of dopamine.

Dosages and Approvals:

Safinamide (Tradename: Xadago) is indicated for the treatment of adult patients with idiopathic Parkinson's disease (PD) as add-on therapy to a stable dose of Levodopa (L-dopa) alone or in combination with other PD medicinal products in mid-to late-stage fluctuating patients. Treatment with Safinamide should be started at 50 mg per day. This daily dose may be increased to 100 mg/day on the basis of individual clinical need [6].

Safinamide may be taken with or without food.

Safinamide use in patients with severe hepatic impairment is contraindicated. No dose adjustment is required in patients with mild hepatic impairment. The lower dose of 50 mg/day is recommended for patients with moderate hepatic impairment. If patients progress from moderate to severe hepatic impairment Safinamide should be stopped.

Safinamide was discovered by Farmitalia Carlo Erba, later taken over by Pharmacia and UpJohn (P and U). P and U took Safinamide to Phase I trials with potential treatment for epilepsy. At the end of 1998, Newron Pharmaceuticals acquired the rights and intellectual property from Pharmacia Corporation. In 2004, Newron initiated Phase III trials of Safinamide for treating Parkinson's disease, and in 2006 Newron signs global development and commercialisation agreement for Safinamide with Merck Serono. In 2011, Merck Serono backed out of the deal and transferred all rights to Newron.

Since 2012, Newron is in strategic collaboration and licence agreement with Zambon for the worldwide development and commercialization of Safinamide (excluding Japan and key Asian territories) and with Meiji Seika Pharma, under which Meiji Seika acquired the rights to develop and commercialize Safinamide in Japan and key Asian territories.

Reported Activities for Safinamide:

Safinamide (S-enantiomer) is a highly selective and reversible inhibitor of MAO-B (IC₅₀ rat MAO-B = 0.098 uM) enzyme with minimal effect on MAO-A enzyme (IC₅₀ rat MAO-A = 580 uM) and increases the level of endogenous and exogenous dopamine. Almost complete inhibition of MAO-B is achieved with a dose of 0.3 mg/kg of safinamide in humans. The selectivity of safinamide for MAO-B is so high that even at doses of 10 mg/kg, no inhibition of MAO-A was observed.

IC₅₀ (Inhibition of rat MAO-B activity) = 0.098 uM

IC₅₀ (Inhibition of rat MAO-A activity) = 580 uM

Selectivity Index (ratio of IC₅₀ value of MAO-A by that of MAO-B) = 5918

R enantiomer has the following activities:

IC₅₀ (Inhibition of rat MAO-B activity) = 0.45 uM

IC₅₀ (Inhibition of rat MAO-A activity) = 42 uM

Selectivity Index (ratio of IC₅₀ value of MAO-A by that of MAO-B) = 93

 Summary

Common name: EMD 1195686; FCE 26743; ME2125; NW 1015; PNU 151774; PNU 151774E; Safinamide; Safinamide mesilate; Safinamide mesylate

Trademarks: Xadago

Molecular Formula: C17H19FN26O2

CAS Registry Number: 133865-89-1; 202825-46-5 (mesylate)

CAS Name: (S)-2-((4-((3-fluorobenzyl)oxy)benzyl)amino)propanamide

Molecular Weight: 302.34

SMILES: C[C@H](NCC1=CC=C(OCC2=CC=CC(F)=C2)C=C1)C(N)=O

InChI Key: NEMGRZFTLSKBAP-LBPRGKRZSA-N

InChI: InChI=1S/C17H19FN2O2/c1-12(17(19)21)20-10-13-5-7-16(8-6-13)22-11-14-3-2-4-15(18)9-14/h2-9,12,20H,10-11H2,1H3,(H2,19,21)/t12-/m0/s1

Mechanism of Action: Monoamine Oxidase-B Inhibitor; Dopamine Uptake Inhibitor; Glutamate Release Inhibitor; Calcium Channel Antagonist; Sodium Channel Antagonist

Activity: Treatment of Parkinson’s Disease; Antiepileptics; Dopaminergic Agents; Nervous System Drugs; Anti-Parkinson Drugs

Status: Launched 2016 (EU)

Chemical Class: Small molecules; Flourine containing; Amides, Benzylamines; Ether containing; Fluorobenzenes; L-Alaninamide derivative

Originator: Farmitalia Carlo Erba / Newron Pharmaceuticals

Safinamide Synthesis

EP2474521A1: It is one of the earliest reported synthetic procedures. The yields are quantitative with desired enantiomer.

A mixture of 3-fluorobenzyl chloride (2.86 g, 19.80 mmol) 4-hydroxybenzaldehyde (3.03 g, 24.80 mmol), K₂CO₃ (10.30 g, 74.50 mmol), NaI (137.1 mg, 0.91 mmol), and ethanol, (40 ml) is heated to reflux in 70 minutes and kept at reflux temperature for 4 hours and 15 minutes. After working up the reaction mixture, 4-(3-fluorobenzyloxy)benzaldehyde, is isolated as a yellow oil in 95% yield.

(S)-2-[4-(3-Fluorobenzyloxy)benzylamino]propanamide (Safinamide) is prepared by reacting 4-(3-fluorobenzyloxy)benzaldehyde (10 mmol), and L-alaninamide hydrochloride (1.37g, 11mmol) followed by reduction with NaBH₃CN(0.50 g, 8 mmol). After working up the reaction mixture and purification by flash-chromatography, (S)-2[4-(3-fluorobenzyloxy)benzylamino]propanamide is isolated as white solid in 68.7% yield.

See also Ref. 8.

The 4-(3-fluorobenzyloxy)benzaldehyde intermediate can also be synthesized using the following procedure: 3-fluorobenzyl chloride (14.5 g, 100 mmol) is added under stirring and under nitrogen atmosphere to a solution of 4-hydroxybenzaldehyde (12.2 g, 100 mmol) and of NaOH (4.0g, 100 mmol) in ethanol (100 ml). The mixture is gradually heated in 25 minutes to reflux and stirred at reflux temperature for 6 hours and 20 minutes. The reaction mixture is filtrated and then concentrated at reduced pressure to obtain 4-(3-fluorobenzyloxy)benzaldehyde (23.4 g) as a yellow solid residue. Dichloromethane (250 ml) is added to the residue, the insoluble is filtered and the resulting solution is concentrated under reduced pressure to provide 4-(3-fluorobenzyloxy)benzaldehyde as a yellow solid, in 80.4% yield [J Agric Food Chem 1979, 27, 4].

WO2014178083A1: A highly enantioselective synthesis of the anti-Parkinson agent Safinamide from simple, commercially available, starting materials is described. Safinamide produced by the process have high enantiopurity of greater than 98% ee. The process looks promising for further studies or to be used as an industrial process for preparation. See also Ref. 10.

Intermediate 1:

Intermediate 2:

Final Synthesis:

J Med Chem 2007, 50(20), 4909-4916: The article reports solid phase synthesis for Safinamide and its various analogues. The yield are quantitative with greater than 98% ee.

Identifications:

1H NMR (Estimated) for Safinamide

Experimental: ¹H NMR (200 MHz, CDCl₃): δ_H = 1.34 (d, J = 6.9 Hz, 3 H), 2.49 (br s, 2 H), 3.19 - 3.30 (q, J = 6.8 Hz, 1 H), 3.71 (dd, J = 19.4, 3.9 Hz, 2 H), 5.05 (s, 2 H), 5.85 (br s, 1 H), 6.95 (d, J = 8.7 Hz, 2 H), 7.00 - 7.06 (m, 1 H), 7.13 - 7.24 (m, 4 H), 7.29 - 7.40 (m, 1 H).

13C NMR (Estimated) for Safinamide

Experimental: ¹³C NMR (50 MHz, CDCl₃): δ_c = 178.3 (CO), 165.4 (C), 157.7 (C), 139.6 (C), 132.1 (C), 130.2 (CH), 129.3 (CH, 2 C), 122.7 (CH), 114.9 (CH, 2 C), 114.6 (CH), 113.9 (CH), 69.2 (CH₂), 57.5 (CH), 51.9 (CH₂), 19.6 (CH₃).

Sideeffects: The most common adverse events (AEs) (incidence less than 10 %) considered to be related to Safinamide included dyskinesia, insomnia, somnolence, dizziness, headache, PD or PD worsening, cataract, orthostatic hypotension, nausea, backpains, weight loss and falls.

Although transient dyskinesia was more common with Safinamide than with placebo, it was usually mild and did not require discontinuation of therapy.

Animal studies indicate that Safinamide treatment is associated with adverse reactions on female rat reproductive performance and sperm quality. Male rat fertility is not affected. No clinical data for Safinamide on exposed pregnancies is available. Animal studies have shown adverse reactions when exposed to Safinamide during pregnancy or lactation. Women of childbearing potential should be advised not to become pregnant during Safinamide therapy. Safinamide should not be given during pregnancy.

Safinamide use in patients with severe hepatic impairment is contraindicated. No dose adjustment is required in patients with mild hepatic impairment. The lower dose of 50 mg/day is recommended for patients with moderate hepatic impairment. If patients progress from moderate to severe hepatic impairment Safinamide should be stopped.

Safinamide should not be administered to patients with ophthalmological history that would put them at increased risk for potential retinal effects (e.g., albino patients, family history of hereditary retinal disease, retinitis pigmentosa, any active retinopathy, or uveitis).

Others

Safinamide also blocks Na⁺ / Ca²⁺ channels, which finally cause inhibition of glutamate release. This feature is similar to the well-studied antiparkinsonian efficacy of Amantadine. Thus, this unique combination of two modes of actions offers the potential of a symptomatic relief of motor features in PD patients in one drug. Safinamide also inhibits sigma-1 receptors in the endoplasmic reticulum of cells. They are thought to be multifunctional regulatory proteins with a role in CNS development, plasticity and neurodegeneration. Combination of the two activities makes Safinamide a putative antiepileptic [1-4].

In various PD trials, addition of Safinamide has improved both motor scores and duration of ‘on’ similar to other monoamine-oxidase B inhibitors, with an added benefit of not increasing troublesome dyskinesias.

Safinamide has shown to improve depression and in a single sub-study has shown to improve cognitive functions.

Putative disease-modifying neuroprotective properties of Safinamide, independent of MAO-B inhibition, have been investigated in in vitro and in vivo models not only for PD, but also in models for multiple sclerosis.

References:

1. Schapira, A. H. Safinamide in the treatment of Parkinson's disease. Expert Opin Pharmacother 2010, 11(13), 2261-2268. (FMO only)

2. Kandadai, R. M.; et. al. Safinamide for the treatment of Parkinson's disease. Expert Rev Clin Pharmacol 2014, 7(6), 747-759. (FMO only)

3. Muller, T. Current status of safinamide for the drug portfolio of Parkinson’s disease therapy. Expert Rev Neurother 2013, 13(9), 969-977. (FMO only)

4. Leonetti, F.; et. al. Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase. J Med Chem 2007, 50(20), 4909-4916. (FMO only)

5. Deeks, E. D. Safinamide: first global approval. Drugs 2015, 75(6), 705-711. (FMO only)

6. Safinamide. EU Approval

7. Barbanti, E.; et. al. High purity degree 2-[4-(3- and 2-fluorobenzyloxy)benzylamino]propanamides for use as medicaments and pharmaceutical formulations containing them. EP2474521A1

8. Pevarello, P.; et. al. Synthesis and anticonvulsant activity of a new class of 2-[(arylalky)amino]alkanamide derivatives. J Med Chem 1998, 41(4), 579-590. (FMO only)

9. Muthukrishnan, M.; et. al. An improved synthesis of anti-parkinson agent. WO2014178083A1

10. Reddi, A.; et. al. A New Enantioselective Synthesis of the Anti-Parkinson Agent Safinamide. Synthesis 2014, 46(13), 1751-1756. (FMO only)

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